The usefulness of those derivatives of polysaccharides which assume random coil conformation depends primarily on their average degree of substitution and is only slightly affected by the differences in substitution patterns. Polysaccharide derivatives with an ordered conformation and derivatives of cyclic oligosaccharides (e.g., .alpha.-, .beta.-, or .gamma.-cyclodextrins, see FIGS. 1-3), which are de facto ordered by the presence of a cycle, present a different problem; there the substitution pattern may profoundly affect their usefulness. The shape of cyclodextrins is a toroid: on the narrower side of the toroids (due to the perspective distortion the outside of macrocycles in FIGS. 1-3) are located all primary hydroxyls and on the wider sides are the secondary hydroxyls. Thus, substitution on secondary hydroxyls puts the substituents close to the wider entry of the cavity of the toroid, whereas substitutions on the primary hydroxyls are close to the narrower entry. The principal use of cyclodextrins is in inclusion complexation: a guest lipophilic compound is accepted into the toroidal cavity of the host compound, i.e., of the cyclodextrin. This process is bound to be affected by specific changes at the entry sites of the host molecule. That was well demonstrated using chemically pure cyclodextrin derivatives. These compounds were prepared by multi-step synthesis requiring multiple extensive purifications and thus are available only in small quantities and at a great price. In many applications the chemical purity (individuality) of cyclodextrin derivatives is not required or may even be of a detriment. Using mixtures of cyclodextrins is often preferred since these usually do not crystallize and thus have much higher solubilities and are also better suited as coatings.
Cyclodextrins, of structures depicted in FIGS. 1-3 similarly to other carbohydrates, react with epoxides yielding mixtures of oligosubstituted hydroxyalkylcyclodextrins. The latter compounds were first disclosed in a patent (Gramera and Caimi, Cyclodextrin Polyethers and Their Production, U.S. Pat. No. 3,459,731, Aug. 5, 1969); alkali catalyzed heterogenous reaction in pressure vessel was used in that work. Later these mixtures were prepared by reaction of epoxides with cyclodextrins in a homogenous reaction in aqueous alkali and the products found eminently useful for pharmaceutical purposes and this use was protected with patents (Pitha, Administration of Sex Hormones in the Form of Hydrophilic Cyclodextrin Derivatives, U.S. Pat. No. 4,596,795, June 24, 1986; Pitha, Pharmaceutical Preparations Containing Cyclodextrin Derivatives, U.S. Pat. No. 4,727,064, Feb. 23, 1988; B. W. W. Muller and U. Brauns, Eur. Patent Appl. No. 115,965, 1983; B. W. W. Muller, Derivatives of gamma-cyclodextrin, U.S. Pat. No. 4,764,604, Aug. 16, 1988 and comp. European patent application 86200334.0; B. W. W. Muller and U. Brauns, Int. J. Pharm. 26, 77, 1985; B. W. W. Muller and U. Brauns, J. Pharm. Res. 309, 1985; B. W. W. Muller and U. Brauns, J. Pharm. Sci. 75, 571, 1986). Hydroxyalkylcyclodextrins were also prepared by reaction of cyclodextrins with ethylene or propylene carbonate catalyzed by potassium carbonate (R. B. Friedman, Modified Cyclodextrins, abstract B6 of the 4th International Symposium on Cyclodextrins, April 1988, Munich, West Germany and German DE 3712246. Furthermore, preparation of mixed alkyl and hydroxyalkylcyclodextrins was the subject of two patent applications (L. Brandt and U. H. Felcht, Eur. Patent Appl. EP146,841 and EP147,685, which correspond to U.S. Pat. Nos. 4,582,900 and 4,638,058). The '900 and '058 patents do not contain any data on distribution of the substituents. The multicomponent mixtures of hydroxyalkylcyclodextrins could be characterized using mass spectrometry, as far as number of substituents per cyclodextrin is concerned-see FIGS. 4-5. Each of the peaks in such a spectrum corresponds to a certain degree of substitution, but since there is a great number of possible isomeric compounds at any degree of substitution, the mixtures are only partially characterized by direct mass spectrometry. An advance in characterization was obtained by hydrolysis of hydroxpropylcyclodextrin mixtures and evaluation of the hydroxpropylglucose mixtures thus obtained by mass spectrometry (T. Irie, K. Fukunaga, A. Yoshida, K. Uekama, H. M. Fales, and J. Pitha, Pharmaceut. Res. 5, 713-717, 1988). These results show that the substituents in hydroxpropylcyclodextrins are not evenly distributed between the glucose residues. A large number of hydroxyalkylcyclodextrins has been prepared and characterized in this manner and the average degree of substitution was found to depend primarily on the ratio of reagents used. These quite diverse reaction conditions yielded mixtures with a rather similar distribution of degree of substitution (Pitha et al., Int. J. Pharm. 29: 73-82, 1986; Irie et al., Pharmaceut. Res. 5: 713-717, 1988). Consequently, the reaction conditions (i.e., strength of alkali added) were chosen primarily on the basis of convenience of manipulation of the mixtures. In different protocols (Pitha et al., Int. J. Pharm. 29: 73-82, 1986; Irie et al., Pharmaceut. Res. 5: 713-717, 1988) the concentration of sodium hydroxide solution, which is used as a solvent for the other component, ranged between 5-17% W/W. At concentrations lower than these the reaction proceeds sluggishly; at higher concentrations the solubility of .alpha.-cyclodextrin decreases and also the removal of sodium hydroxide after the reaction becomes tedious. In production of hydroxyalkylcyclodextrins the practical range of the concentrations of sodium hydroxide solution used as a solvent were 5-17% and there was no incentive to venture outside of this range.